Professional Information
Gemfibrozil (Systemic)
VA CLASSIFICATION
Primary: CV359
Commonly used brand name(s): Apo-Gemfibrozil; Gen-Fibro; Lopid; Novo-Gemfibrozil; Nu-Gemfibrozil.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antihyperlipidemic—
Indications
Accepted
Hyperlipidemia (treatment)—Gemfibrozil is indicated in the treatment of hyperlipidemia and to reduce the risk of coronary heart disease only in those patients with type IIb hyperlipidemia without history of or symptoms of existing coronary heart disease, who have not responded to diet, exercise, weight loss, or other pharmacologic therapy (bile acid sequestrants and niacin) alone and who have the triad of low high density lipoprotein (HDL) cholesterol levels, elevated low density lipoprotein (LDL) cholesterol levels, and elevated triglycerides {12}.
—Gemfibrozil is also recommended for use in patients with severe primary hyperlipidemia (types IV and V hyperlipidemia) and a significant risk of coronary artery disease, abdominal pain typical of pancreatitis, or pancreatitis, who have not responded to diet or other measures alone {01}. Its use is limited in type III hyperlipidemia because of its limited effect on cholesterol concentrations. It is not useful in the treatment of type I hyperlipidemia.
—Gemfibrozil is not indicated for treatment of patients with type IIa hyperlipidemia or patients with low HDL cholesterol as their only lipid abnormality because the potential benefits do not outweigh the risks {01} {12}.
—Caution and close observation are recommended in patients with high triglyceride concentrations, since in some of these patients treatment with gemfibrozil is associated with significant increases in low density lipoprotein (LDL)-cholesterol concentrations {01}.
—For additional information on initial therapeutic guidelines related to the treatment of hyperlipidemia, see Appendix III.
—Gemfibrozil is not recommended for community-wide prevention of ischemic heart disease.
—Studies have suggested that control of elevated cholesterol and triglycerides may not lessen the danger of cardiovascular disease and mortality, although incidence of nonfatal myocardial infarctions may be decreased.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
250.34
Mechanism of action/Effect:
Gemfibrozil reduces plasma triglyceride (very low–density lipoprotein [VLDL]) concentrations and increases high-density lipoprotein (HDL) concentrations. Although gemfibrozil may slightly reduce total and low-density lipoprotein (LDL) cholesterol concentrations, use of gemfibrozil in patients with elevated triglycerides associated with type IV hyperlipidemia often results in significant increases in LDL; LDL concentrations are not significantly affected by gemfibrozil in patients with Type IIb hyperlipidemia (although HDL is significantly increased) {01}. The mechanism of this action is not completely understood but may involve inhibition of peripheral lipolysis; reduced hepatic extraction of free fatty acids, which reduces hepatic triglyceride production {01}; inhibition of synthesis and increased clearance of VLDL carrier, apolipoprotein B, which also reduces VLDL production {01} {03}; and, according to animal studies, reduced incorporation of long-chain fatty acids into newly formed triglycerides, accelerated turnover and removal of cholesterol from the liver (stimulates incorporation of cholesterol precursors into liver sterols), and increased excretion of cholesterol in the feces. {01} {06}
Absorption:
Well absorbed from gastrointestinal tract. {01} {06}
Biotransformation:
Hepatic.
Half-life:
Single dose—1.5 hours.
Multiple doses—1.3 hours. {04}
Onset of action:
Reduction of plasma VLDL concentrations—2 to 5 days.
Time to peak concentration:
1 to 2 hours. {04} {06}
Time to peak effect:
Reduction of plasma VLDL concentrations—4 weeks (major effect; further decreases occur over several months).
Elimination:
Renal (70%; largely unchanged)/fecal (6%). {04}
Precautions to Consider
Carcinogenicity/Tumorigenicity
During long term follow-up of patients in the Helsinki Heart Study, there was a trend toward an increased incidence of basal cell carcinomas and deaths attributed to cancer in the group of patients originally randomized to gemfibrozil. {12} However, these data did not reach statistical significance. {12}
Long-term studies in male rats have shown gemfibrozil to have a tumorigenic effect. Studies in rats given gemfibrozil for prolonged periods found an increased incidence of benign and malignant hepatic tumors in male and female rats, as well as benign testicular (Leydig cell) tumors in male rats, at doses of 1 and 10 times the human dose {01}.
Pregnancy/Reproduction
Fertility—
Studies in male rats given gemfibrozil at doses 0.6 to 2 times the human dose (based on surface area) for 10 weeks revealed a dose-related decrease in fertility. {12}
Pregnancy—
Studies in humans have not been done. {12}
Studies in female rats given gemfibrozil at 0.6 to 2 times the human dose (based on surface area) before and throughout gestation resulted in a dose-related decrease in conception rate and an increase in skeletal variations, including anophthalmia. At the high dose level an increase in stillbirths and reduction in pup weight during lactation were observed. In addition, similar doses given to female rats from gestation day 15 through weaning resulted in decreased birth weights and pup growth suppression during lactation. {12}
Gemfibrozil, given at doses 1 to 3 times the human dose (based on surface area) to female rabbits during organogenesis, caused decreased litter sizes and, at the high dose, an increased incidence of parietal bone variations. {12}
FDA Pregnancy Category C.
Breast-feeding
It is not known whether gemfibrozil is excreted in breast milk. Problems in humans have not been documented; however, any decision regarding breast-feeding during therapy should take into account that gemfibrozil has a tumorigenic effect in rats. {12}
Pediatrics
Appropriate studies on the relationship of age to the effects of gemfibrozil have not been performed in the pediatric population. However, use in children under 2 years of age is not recommended since cholesterol is required for normal development. {07}
Geriatrics
No information is available on the relationship of age to the effects of gemfibrozil in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving gemfibrozil {02}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
» Anticoagulants, coumarin- or indandione-derivative (concurrent use with gemfibrozil may significantly increase the anticoagulant effect of these medications; adjustment of anticoagulant dosage based on frequent prothrombin-time determinations is recommended {01} {06} {12})
Chenodiol or{10}
Ursodiol{11} (effect may be decreased when chenodiol or ursodiol is used concurrently with gemfibrozil, which tends to increase cholesterol saturation of bile)
» Lovastatin (concurrent use with gemfibrozil may be associated with an increased risk of rhabdomyolysis, significant increases in creatine kinase [CK] concentrations, and myoglobinuria that leads to acute renal failure; may be seen as early as 3 weeks or as late as several months after initiation of combined therapy; monitoring of CK has not been shown to prevent severe myopathy or renal damage {01} {08} {09} {12})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Alkaline phosphatase, serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Bilirubin, serum and
Creatine kinase (CK), plasma and
Lactate dehydrogenase (LDH), serum (concentrations may be increased, indicating liver function abnormalities)
Hematocrit and
Hemoglobin concentrations and
Leukocyte counts (may be mildly decreased, but usually stabilize with continued administration)
Potassium (serum concentrations may be decreased)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Primary biliary cirrhosis (use of gemfibrozil may further raise the cholesterol)
Risk-benefit should be considered when the following medical problems exist
Gallbladder disease or
Gallstones (increased risk of biliary complications, including possible formation of gallstones {01})
» Hepatic function impairment (reduced biotransformation; reduced dosage is recommended {01})
» Renal function impairment, severe (reduced clearance leads to increased incidence of side effects; reduced dosage is recommended {01})
(gemfibrozil may worsen pre-existing renal insufficiency {12})
Sensitivity to gemfibrozil
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Blood counts, complete and
Cholesterol, serum and
Liver function tests and
Triglycerides, serum (determinations recommended prior to initiation of therapy and at periodic intervals during therapy {01})
Side/Adverse Effects
Note: Because of the chemical, pharmacologic, and clinical similarity of gemfibrozil to clofibrate, the possibility of similar long-term effects should be kept in mind. Studies with clofibrate have associated long-term use of the medication with an increased incidence of deaths from noncardiovascular causes and have also found a greatly increased incidence of cholelithiasis and cholecystitis requiring surgery in clofibrate users (see Clofibrate [Systemic]). In addition, studies have suggested that control of elevated cholesterol and triglycerides may not lessen the danger of cardiovascular disease and mortality, although incidence of nonfatal myocardial infarctions may be decreased.
Subcapsular bilateral cataracts and unilateral cataracts have been reported in 10% and 6.3%, respectively, of male rats given 10 times the human dose {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for immediate medical attention
Incidence rare
Anemia or leukopenia (cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination){01}
gallstones (severe stomach pain with nausea and vomiting)
myositis (muscle pain, unusual tiredness or weakness){01}
Note: Gemfibrozil may increase cholesterol secretion into the bile. {01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Stomach pain, gas, or heartburn{01}
Incidence less frequent {01}
Diarrhea
nausea or vomiting
skin rash
unusual tiredness
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Gemfibrozil (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
Potential serious toxicity because of similarity to clofibrate
» Diet as preferred therapy
» Conditions affecting use, especially:
Sensitivity to gemfibrozil
Pregnancy—High doses in animals cause birth defects and an increase in fetal deaths
Breast-feeding—High doses associated with increased incidence of tumors in rats; consider when deciding whether to breast-feed
Use in children—Not recommended in children under 2 years of age since cholesterol is required for normal development
Other medications, especially lovastatin or oral anticoagulants
Other medical problems, especially primary biliary cirrhosis, hepatic function impairment, or severe renal function impairment
Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed
Taking 30 minutes before morning and evening meal
» Compliance with prescribed diet
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses
» Proper storage
Precautions while using this medication
» Importance of close monitoring by physician
» Checking with physician before discontinuing medication; blood lipid concentrations may increase significantly
Side/adverse effects
Signs of potential side effects, especially gallstones, leukopenia, anemia, and myositis
General Dosing Information
If response is inadequate after 3 months of treatment, gemfibrozil therapy should be withdrawn {01}.
When gemfibrozil is discontinued, an appropriate hypolipidemic diet and monitoring of serum lipids are recommended until the patient stabilizes, since a rise in serum triglyceride and cholesterol concentrations to the original base may occur.
If results of hepatic function tests rise significantly or show significant abnormalities, it is recommended that gemfibrozil therapy be withdrawn and not resumed; laboratory abnormalities are usually reversible.
If gallstones are found, gemfibrozil therapy should be withdrawn {01}.
If patients receiving gemfibrozil experience muscle pain or weakness, evaluation for myositis (including serum CK determinations) is recommended. It is recommended that gemfibrozil be withdrawn if myositis is suspected or diagnosed {01}.
Diet/Nutrition
Gemfibrozil should be taken 30 minutes before the morning and evening meals. {12}
Oral Dosage Forms
GEMFIBROZIL CAPSULES USP
Usual adult dose
Antihyperlipidemic
Oral, 1.2 grams a day in two divided doses thirty minutes before the morning and evening meals {04}.
Usual pediatric dose
Dosage has not been established.
Strength(s) usually available
U.S.—
Not commercially available.
Canada—
300 mg (Rx) [Lopid] [Apo-Gemfibrozil] [Gen-Fibro] [Nu-Gemfibrozil][Generic]{16}
Packaging and storage:
Store below 30 °C (86 °F), unless otherwise specified by manufacturer. Store in a tight container.
GEMFIBROZIL TABLETS
Usual adult dose
Antihyperlipidemic
Oral, 1.2 grams a day in two divided doses thirty minutes before the morning and evening meals {01} {12}.
Usual pediatric dose
Dosage has not been established.
Strength(s) usually available
U.S.—
600 mg (Rx) [Lopid (scored) (methylparaben) (propylparaben)][Generic]{17}
Canada—
600 mg (Rx) [Lopid] [Apo-Gemfibrozil] [Gen-Fibro] [Novo-Gemfibrozil] [Nu-Gemfibrozil][Generic]{16}
Packaging and storage:
Store below 30 °C (86 °F), unless otherwise specified by manufacturer. Store in a tight container.
Revised: 08/12/1998
References
Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.
- Lopid package insert (Parke-Davis—US), Rec 1/89.
- General concept per Geriatrics Advisory Panel, 1990 revision.
- Kesaniemi Y, Grundy S. Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man. JAMA 1984; 251(17): 2241-6.
- Lopid product information (Parke-Davis—Canada), Rev 11/88, Rec 4/89.
- Laustiola K et al. Gemfibrozil decreases platelet reactivity in patients with hypercholesterolemia during physical stress. Clin Pharmacol Ther 1988; 43(3): 302-7.
- Todd PN, Ward A. Gemfibrozil: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidemia. Drugs 1988; 36: 314-39.
- Panel comment, 1990 revision cycle.
- Pierce L, Wysowski K, Gross T. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264(1): 71-5.
- Marais G, Larson K. Rhabdomyolysis and acute renal failure induced by combination lovastatin and gemfibrozil. Ann Intern Med 1990; 112(3): 228-30.
- Chenix product information (Reid-Rowell—US), Rec 10/88.
- Actigall product information (Ciba—US), Rev 6/88, Rec 1989.
- Lopid package insert (Parke-Davis—US), Rev 4/92, Rec 7/92.
- National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994; 89(3): 1329-445.
- Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987; 2: 10-32.
- Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987; 317: 1237-45.
- Health Canada Drug Product Database (DPD) [online database]. Cited June 22, 1998. Available from: URL: http://www.hc-sc.gc.ca/english/search.htm.
- Red book 1998. Montvale, NJ: Medical Economics Company; 1998. p. 323-4.
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